A Mutation in the Beta 3 Subunit of the Cardiac Sodium Channel Associated with Brugada ECG Phenotype

Overview

Journal Circ Cardiovasc Genet

Specialties Cardiology & Vascular Diseases
Genetics

Date 2009 Dec 25

PMID 20031595

Citations 103

Authors

Dan Hu

Hector Barajas-Martinez

Elena Burashnikov

Michael Springer

Yuesheng Wu

Andras Varro

Ryan Pfeiffer

Tamara T Koopmann

Jonathan M Cordeiro

Alejandra Guerchicoff

Guido D Pollevick

Charles Antzelevitch

Affiliations

Soon will be listed here.

Abstract

Background: Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.

Methods And Results: A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the beta 3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of Na(V)beta 3 in human ventricular myocardium.

Conclusions: Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNa(v)1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.

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References

Chen Q, Kirsch G, Zhang D, Brugada R, Brugada J, Brugada P . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998; 392(6673):293-6. DOI: 10.1038/32675. View

Qu Y, Isom L, Westenbroek R, Rogers J, Tanada T, McCormick K . Modulation of cardiac Na+ channel expression in Xenopus oocytes by beta 1 subunits. J Biol Chem. 1995; 270(43):25696-701. DOI: 10.1074/jbc.270.43.25696. View

Makita N, Bennett Jr P, George Jr A . Voltage-gated Na+ channel beta 1 subunit mRNA expressed in adult human skeletal muscle, heart, and brain is encoded by a single gene. J Biol Chem. 1994; 269(10):7571-8. View

Watanabe H, Koopmann T, Scouarnec S, Yang T, Ingram C, Schott J . Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008; 118(6):2260-8. PMC: 2373423. DOI: 10.1172/JCI33891. View

Isom L, De Jongh K, Patton D, Reber B, Offord J, Charbonneau H . Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science. 1992; 256(5058):839-42. DOI: 10.1126/science.1375395. View

Schulze-Bahr E, Eckardt L, Breithardt G, Seidl K, Wichter T, Wolpert C . Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat. 2004; 21(6):651-2. DOI: 10.1002/humu.9144. View

Adachi K, Toyota M, Sasaki Y, Yamashita T, Ishida S, Ohe-Toyota M . Identification of SCN3B as a novel p53-inducible proapoptotic gene. Oncogene. 2004; 23(47):7791-8. DOI: 10.1038/sj.onc.1208067. View

Wan X, Wang Q, Kirsch G . Functional suppression of sodium channels by beta(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation. J Mol Cell Cardiol. 2000; 32(10):1873-84. DOI: 10.1006/jmcc.2000.1223. View

Antzelevitch C, Pollevick G, Cordeiro J, Casis O, Sanguinetti M, Aizawa Y . Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007; 115(4):442-9. PMC: 1952683. DOI: 10.1161/CIRCULATIONAHA.106.668392. View

10.

Antzelevitch C . Brugada syndrome. Pacing Clin Electrophysiol. 2006; 29(10):1130-59. PMC: 1978482. DOI: 10.1111/j.1540-8159.2006.00507.x. View

11.

Meadows L, Malhotra J, Stetzer A, Isom L, Ragsdale D . The intracellular segment of the sodium channel beta 1 subunit is required for its efficient association with the channel alpha subunit. J Neurochem. 2001; 76(6):1871-8. DOI: 10.1046/j.1471-4159.2001.00192.x. View

12.

Yu F, Westenbroek R, Silos-Santiago I, McCormick K, Lawson D, Ge P . Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2. J Neurosci. 2003; 23(20):7577-85. PMC: 6740763. View

13.

Ko S, Lenkowski P, Lee H, Mounsey J, Patel M . Modulation of Na(v)1.5 by beta1-- and beta3-subunit co-expression in mammalian cells. Pflugers Arch. 2004; 449(4):403-12. DOI: 10.1007/s00424-004-1348-4. View

14.

Brugada P, Brugada J . Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992; 20(6):1391-6. DOI: 10.1016/0735-1097(92)90253-j. View

15.

Sjoblom T, Jones S, Wood L, Parsons D, Lin J, Barber T . The consensus coding sequences of human breast and colorectal cancers. Science. 2006; 314(5797):268-74. DOI: 10.1126/science.1133427. View

16.

Meadows L, Isom L . Sodium channels as macromolecular complexes: implications for inherited arrhythmia syndromes. Cardiovasc Res. 2005; 67(3):448-58. DOI: 10.1016/j.cardiores.2005.04.003. View

17.

An R, Wang X, Kerem B, Benhorin J, Medina A, Goldmit M . Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. Circ Res. 1998; 83(2):141-6. DOI: 10.1161/01.res.83.2.141. View

18.

Remme C, Wilde A, Bezzina C . Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations. Trends Cardiovasc Med. 2008; 18(3):78-87. DOI: 10.1016/j.tcm.2008.01.002. View

19.

Isom L, Ragsdale D, De Jongh K, Westenbroek R, Reber B, Scheuer T . Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell. 1995; 83(3):433-42. DOI: 10.1016/0092-8674(95)90121-3. View

20.

McClatchey A, Cannon S, Slaugenhaupt S, Gusella J . The cloning and expression of a sodium channel beta 1-subunit cDNA from human brain. Hum Mol Genet. 1993; 2(6):745-9. DOI: 10.1093/hmg/2.6.745. View